过表达 MD1 可通过 TLR4/STAT3 信号通路改善糖尿病心肌病的病理性心肌重塑。

IF 3.8 3区 医学 Q2 CELL BIOLOGY Molecular and Cellular Endocrinology Pub Date : 2024-06-13 DOI:10.1016/j.mce.2024.112315
Caijie Shen , Shuwen Yang , Nan Wu , Wang Jian , Tingsha Du , Huimin Chu , Weiping Du
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引用次数: 0

摘要

糖尿病心肌病(DCM)的特点是氧化损伤和炎症反应。髓系分化蛋白 1(MD1)具有抗氧化和抗炎特性。然而,MD1 在 DCM 中的具体作用仍有待阐明。本研究旨在探讨 MD1 在 DCM 中的作用并阐明其潜在机制。我们采用功能增益法来探讨 MD1 在 DCM 中的参与。通过注射链脲佐菌素(STZ)诱导 MD1 转基因(MD1-TG)小鼠及其野生型(WT)小鼠患糖尿病。此外,我们还利用暴露于高葡萄糖水平的 H9c2 细胞建立了糖尿病细胞模型。我们进行了全面的评估,包括病理分析、超声心动图、心电图和分子评估,以阐明 MD1 在 DCM 中的潜在机制。值得注意的是,MD1在STZ诱导的糖尿病小鼠心脏中表达减少。过表达 MD1 能显著改善这些小鼠的心功能,并明显抑制心室病理性肥厚和纤维化。此外,MD1 的过表达导致心肌活性氧(ROS)积累大幅减少,减轻了心肌氧化应激,降低了炎症相关标志物(如 IL-1β、IL-6 和 TNF-α)的水平。从机理上讲,MD1的过表达抑制了TLR4/STAT3信号通路的激活,这在体内和体外实验中均得到了证实。在 STZ 诱导的糖尿病小鼠体内,MD1 的过表达能显著抑制病理性心脏重塑并改善心脏功能。这种效应主要归因于抑制 TLR4/STAT3 信号通路减少了 ROS 的积累,减轻了心肌氧化应激和炎症反应。
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Overexpression of MD1 ameliorates pathological myocardial remodeling in diabetic cardiomyopathy by TLR4/STAT3 signaling pathway

Diabetic cardiomyopathy (DCM) is characterized by oxidative damage and inflammatory responses. Myeloid differentiation protein 1 (MD1) exhibits antioxidant and anti-inflammatory properties. However, the specific role of MD1 in DCM has yet to be elucidated. This study aims to investigate the role of MD1 in DCM and to elucidate the underlying mechanisms. We utilized a gain-of-function approach to explore the involvement of MD1 in DCM. Diabetes was induced in MD1-transgenic (MD1-TG) mice and their wild-type (WT) counterparts via streptozotocin (STZ) injection. Additionally, a diabetes cell model was established using H9c2 cells exposed to high glucose levels. We conducted comprehensive evaluations, including pathological analyses, echocardiography, electrocardiography, and molecular assessments, to elucidate the underlying mechanisms of MD1 in DCM. Notably, MD1 expression was reduced in the hearts of STZ-induced diabetic mice. Overexpression of MD1 significantly improved cardiac function and markedly inhibited ventricular pathological hypertrophy and fibrosis in these mice. Furthermore, MD1 overexpression resulted in a substantial decrease in myocardial reactive oxygen species (ROS) accumulation, mitigating myocardial oxidative stress and reducing the levels of inflammation-related markers such as IL-1β, IL-6, and TNF-α. Mechanistically, MD1 overexpression inhibited the activation of the TLR4/STAT3 signaling pathway, as demonstrated in both in vivo and in vitro experiments. The overexpression of MD1 significantly impeded pathological cardiac remodeling and improved cardiac function in STZ-induced diabetic mice. This effect was primarily attributed to a reduction in ROS accumulation and mitigation of myocardial oxidative stress and inflammation, facilitated by the inhibition of the TLR4/STAT3 signaling pathway.

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来源期刊
Molecular and Cellular Endocrinology
Molecular and Cellular Endocrinology 医学-内分泌学与代谢
CiteScore
9.00
自引率
2.40%
发文量
174
审稿时长
42 days
期刊介绍: Molecular and Cellular Endocrinology was established in 1974 to meet the demand for integrated publication on all aspects related to the genetic and biochemical effects, synthesis and secretions of extracellular signals (hormones, neurotransmitters, etc.) and to the understanding of cellular regulatory mechanisms involved in hormonal control.
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